The complement system is an ancient arm of innate immunity which is best known for its role as a ?first-line-of-defense? against microbial pathogens. However, complement sits at the center of several important physiological and pathophysiological processes and it is now known that dysregulation of complement contributes significantly to many human autoimmune, inflammatory, and neurodegenerative diseases. In 2016, a landmark study demonstrated that the classical complement pathway mediates neurodegeneration in a mouse model of Alzheimer?s disease and this causal link between complement and Alzheimer?s disease has only been strengthened by follow-up studies. Alzheimer?s disease is a worldwide health crisis, and 14 million Americans are predicted to suffer from this enormously devastating disease by 2050. Currently no cure for Alzheimer?s disease exists and development of new treatments is desperately needed. Although the classical pathway of complement has now been identified as a therapeutic intervention point for Alzheimer?s disease, the existing pipeline of complement-directed drugs is inadequately positioned for this purpose. In this project we address this need by using our recently developed, multidisciplinary, cheminformatics-based approach to discover novel small molecule inhibitors of the classical complement pathway. The first component of complement, C1, is the multi-subunit initiating zymogen of the classical pathway and consists of the pattern recognition molecule C1q in complex with a heterotetrameric arrangement of the serine proteases C1r and C1s. Upon activation by C1r, C1s performs the earliest catalytic steps of the classical complement pathway. Interestingly, C1s requires the molecular context of C1 for this activity. In this project we will use structure-based knowledge to identify C1s-binding small molecules which disrupt the stability of C1s within the C1 complex resulting in classical pathway-specific complement inhibition. To achieve this endpoint we will deploy our recently developed complement- directed cheminformatics-based small molecule drug discovery approach. A large scale in silico screen will be conducted to identify putative C1s-binding drug-like molecules which target key functional ?hot spots? on the C1s surface. Prioritized hit compounds will be validated in vitro using a multifaceted biochemical and functional approach. X-ray crystallography will be used to empirically determine the binding mode of prioritized hit compounds. This project will provide the foundation for structure-based drug design efforts aimed at the development of novel complement-directed therapeutics for treatment of classical pathway-related diseases such as Alzheimer?s disease.